This application is the national phase under 35 U.S.C. xc2xa7371 of PCT International Application No. PCT/JP00/01232 which has an International filing date of Mar. 2, 2000, which designated the United States of America.
The present invention relates to a novel compound useful as a medicament, specifically as an acetylcholinesterase inhibitor, more specifically as an agent for preventing, treating or ameliorating various types of senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder (ADHD), and further specifically as an agent for preventing, treating and ameliorating various senile dementia especially Alzheimer-type senile dementia, and to a process for producing it.
With a rapidly increasing population of the older generation, it is strongly desired to establish a method of treating senile dementia such as Alzheimer-type senile dementia, cerebrovascular dementia and attention deficit hyperactivity disorder.
Development of treating agents for these diseases has been studied from various points of view, and in a prominent point of view, development of acetylcholine precursors and acetylcholinesterase inhibitors is proposed because these diseases are accompanied by a reduction in cholinergic functions in the brain, and actually, such compounds are clinically applied. Typical acetylcholinesterase inhibitors include donepezil hydrochloride (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride), rivastigmine (3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate), metrifonate (dimethyl 2,2,2-trichloro-1-hydroxyethyl)phosphate), tacrine hydrochloride (1,2,3,4-tetrahydro-9-acridinamine), galanthamine hydrobromide, neostigmine, physostigmine etc.
However, among these medicaments, denepezil hydrochloride is only the compound that is confirmed to have a pharmaceutical effect on the diseases in actual clinical application and is recognized to have satisfactory usefulness from the viewpoint of side effects and frequency of administration. The other medicaments have some drawbacks such as poor effects, undesirable side effects, necessity for frequent administration per day, and limited use in an injection because of their inapplicability to oral administration. Therefore, there is no or little choice but to choose denepezil hydrochloride at present. As mentioned above, denepezil hydrochloride is a superior medicament. It is needless to say, however, that the presence of acetylcholinesterase inhibitors having more superior effects would be more preferred for a wider choice of medicaments in clinical application. Accordingly, the object of the present invention is to provide a novel compound useful as a medicament, specifically as an acetylcholinesterase inhibitor, more specifically as an agent for preventing, treating or ameliorating various types of senile dementia, cerebrovascular dementia and attention deficit hyperactivity disorder, and further specifically as an agent for preventing, treating or ameliorating Alzheimer-type senile dementia, and a process for producing it.
The present inventors have extensively studied on various compounds for a long period of time for the development of medicaments having more superior effects and higher safety. As a result, they have found that a novel 4-substituted piperidine compound fluoride represented by the following formula (I), a pharmaceutically acceptable salt thereof or hydrates thereof (provided that 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine, a pharmaceutically acceptable salt thereof and hydrates thereof are excluded) can achieve the above object, and have completed the present invention. 
In the formula, R1 represents any one selected from the group consisting of the following substituents: 
(wherein each R3 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, a C1-6 alkyl group, a C3cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkoxyalkoxy group, a halogeno C1-6 alkyl group, a hydroxy C1-6 alkyl group, a cyano C1-6 alkyl group, a halogeno C1-6 alkoxy group, a hydroxy C1-6 alkoxy group, a cyano C1-6 alkoxy group, a lower acyl group, a nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C1-6 thioalkoxy group; R4 represents hydrogen atom or a C1-6 alkyl group; the bond represented by the following formula:

is a single or double bond; m is 0 or an integer of 1 to 6; n is an integer of 1 to 4; and p is an integer of 1 or 2); and
R2 represents a C3-8 cycloalkylmethyl group, 2,2-(alkylenedioxy)ethyl group or a group represented by the formula: 
(wherein the ring A is benzene ring or a heterocyclic ring; each R1 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkoxyalkoxy group, an aryloxy group, an aralkyloxy group, a halogeno C1-6 alkyl group, a hydroxy C1-6 alkyl group, a cyano C1-6 alkyl group, a halogeno C1-6 alkoxy group, a hydroxy C1-6 alkoxy group, a cyano C1-6 alkoxy group, a lower acyl group, a nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C1-6 thioalkoxy group, and two of the R5 groups may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and q is 0 or an integer from 1 to 5).
That is, the first aspect of the present invention is:
1) a 4-substituted piperidine compound fluoride represented by the above formula (I), a pharmaceutically acceptable salt thereof or hydrates thereof;
2) in the above 1), R1 may be a group represented by the formula: 
wherein R3, m and n have the same meanings as defined above;
(3) in the above 1), R2 may be a group represented by the formula: 
wherein R5 and q have the same meanings as defined above;
4) in the above 3), the ring A may be a group represented by the formula: 
wherein R5 and q have the same meanings as defined above;
5) in the above 3), the ring A may be an aromatic heterocyclic ring;
6) in the above 3), the ring A may be pyridine ring;
7) in the above items 1) to 6), q may be an integer of 1 or 2; and
8) in the above 1), the 4-substituted piperidine compound fluoride may be the one selected from:
(1) 1-benzyl-4-[(5,6-diethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(2) 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl)piperidine;
(3) 1-benzyl-4-[2-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]ethyl]piperidine;
(4) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-fluorobenzyl)piperidine;
(5) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-methylbenzyl)piperidine;
(6) 1-cyclohexylmethyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(7) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(1,3-dioxolan-2-yl)methylpiperidine; and
(8) 1-(4-benzyloxybenzyl)-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(9) 3-(1-benzylpiperidin-4-yl)-2-fluoro-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone;
(10) 3-(1-benzylpiperidin-4-yl)-2,2-difluoro-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone;
(11) 5,7-dihydro-3-[1-fluoro-2-[1-phenylmethyl]-4-piperidinyllethyl]-6H-pyrolo[4,5-f]-1,2-benzisooxasol-6-on;
(12) 5,7-dihydro-3-[1,1-difluoro-2-[1-phenylmethyl]-4-piperidinyl]ethyl]-6H-pyrolo[4,5-f]-1,2-benzisooxasol-6-on;
(13) 1-(2-methyl-6-benzothiazoryl)-3-[1-phenylmethyl]-4-piperidinyl]-2-fluoro-1-propanone; and
(14) 1-(2-methyl-6-benzothiazoryl)-3-[1-phenylmethyl]-4-piperidinyl]-2,2-difluoro-1-propanone.
The second aspect of the present invention is:
9) a pharmaceutical preparation comprising, as an active ingredient, the 4-substituted piperidine compound fluoride of the above 1), a pharmaceutically acceptable salt thereof or hydrates thereof;
10) in the above 9), the pharmaceutical preparation may be an acetylcholinesterase inhibitor;
11) in the above 9), the pharmaceutical preparation may be an agent for treating, preventing or ameliorating various types of senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder; and
12) in the above 11), the various types of senile dementia may be Alzheimer-type senile dementia.
That is, the present invention provides a method for preventing, treating or ameliorating a disease against which acetylcholinesterase inhibition is effective and a method for preventing, treating or ameliorating various types of senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder, by administering a pharmaceutically effective amount of the above pharmaceutical preparation to a patient. The present invention also provides use of the 4-substituted piperidine derivative fluoride, a pharmaceutically acceptable salt thereof or hydrates thereof for producing the above pharmaceutical preparations and a pharmaceutical composition comprising it.
The third aspect of the present invention is:
13) a process for producing the 4-substituted piperidine compound fluoride as described in the above 1), a pharmaceutically acceptable salt thereof or hydrates thereof (provided that 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine, a pharmacologically acceptable salt thereof and hydrates thereof are excluded), which comprises fluorinating the 4-substituted piperidine compound represented by the following formula (II); and, if required, converting it into a salt. 
In the formula, R11 represents any group selected from the following substituents: 
(wherein R3, R4, n, m, p and the bond represented by the following formula:

have the same meanings as defined; and
R2 has the same meanings as defined above.
Further, 14) in the process of the above 13), the flourinating agent may be N-flourobenzenesufonimide, 3-cyclohexyl-2-flouro-2,3-dihydro-3-methyl-1,1-dioxide-1,2-benzisothiazole or 2-flouro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide.
Hereinafter, the symbols, terms etc. used in the present specification are explained and the present invention is illustrated in more detail.
In the specification of the present invention, the chemical structure of the compound may represent a certain isomer or isotope for convenience. However, the present invention involves all isomers (e.g., genometric isomers, optical isomers based on asymmetric carbon atoms, stereoisomers and tautomers), isomeric mixtures and isotopes which may structurally occur. Accordingly, the compound of the present invention is not limited to that described in the formula of convenience, and may be one of or a mixture of the isomers or one of the isotopes. Therefore, in the compound of the present invention, although an asymmetric carbon atom may be included in the molecule and there may occur optically active forms and racemates, the compound of the present invention is not particularly limited to a certain form and may include any of such forms. In addition, various type of crystal polymorphism may also occur. However, the compound of the present invention is not also limited to a certain type of polymorphism and may have a single crystalline morphology or a mixture of two or more types of crystalline morphology and may be in the form of an anhydride or a hydrate.
In the formula (I) above, R1 represents any group selected from the the substituents represented by the following formulae, provided that such a substituent is excluded that provides 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine as the 4-substituted piperidine compound fluoride represented by the formula (I). 
In the formula, each R3 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkoxyalkoxy group, a halogeno C1-6 alkyl group, a hydroxy C1-6 alkyl group, a cyano C1-6 alkyl group, a halogeno C1-6 alkoxy group, a hydroxy C1-6 alkoxy group, a cyano C1-6 alkoxy group, a lower acyl group, a nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C1-6 thioalkoxy group;
R4 represents hydrogen atom or a C1-6 alkyl group;
the bond represented by the following formula:

represents a single or double bond;
m is 0 or an integer of 1 to 6;
n is an integer of 1 to 4; and
p is an integer of 1 or 2.
The xe2x80x9chalogen atomxe2x80x9d represented by the above R3 refers to, for example, fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d represented by the above R3 or R4 refers to an alkyl group having 1 to 6 carbon atoms, including a linear or branched alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, hexyl, 1-methylpropyl, 1-methylbutyl and 2-methylbutyl groups.
The xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d represented by the above R3 refers to a cyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropy, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
The xe2x80x9cC1-6 alkoxy groupxe2x80x9d represented by the above R3 refers to a group in which a xe2x80x9cC1-6 alkyl groupxe2x80x9d as defined above is bonded to an oxygen atom, and includes a linear or branched alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentyloxy and hexyloxy groups.
The xe2x80x9cC1-6 alkoxyalkoxy groupxe2x80x9d represented by the above R3 refers to a group in which the C1-6 alkoxy group as defined above is bound to another xe2x80x9cC1-6 alkoxy groupxe2x80x9d, such as methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy and propoxypropoxy groups.
The xe2x80x9chalogeno C1-6 alkyl groupxe2x80x9d represented by the above R3 refers to a group in which 1 or more of the same or different halogen atoms are bonded to the xe2x80x9cC1-6 alkyl groupxe2x80x9d having the same meaning as defined above, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.
The xe2x80x9chydroxy C1-6 alkyl groupxe2x80x9d represented by the above R3 refers to a group in which one or more hydroxyl groups are bonded to the C1-6 alkyl group as defined above, such as hydroxymethyl, hydroxyethyl and 2,3-hydroxypropyl.
The xe2x80x9ccyano C1-6 alkyl groupxe2x80x9d represented by the above R3 refers to a group in which one or more cyano groups are bonded to the C1-6 alkyl group as defined above, such as cyanomethyl, cyanoethyl and cyanopropyl groups.
The xe2x80x9chalogeno C1-6 alkoxy groupxe2x80x9d represented by the above R3 refers to a group in which an oxygen atom is bonded to the xe2x80x9chalogeno C1-6 alkyl groupxe2x80x9d as defined above; the xe2x80x9chydroxy C1-6 alkoxy groupxe2x80x9d represented by the above R3 refers to a group in which an oxygen atom is bonded to the xe2x80x9chydroxy C1-6 alkyl groupxe2x80x9d as defined above; and the xe2x80x9ccyano C1-6 alkoxy groupxe2x80x9d represented by the above R3 refers to a group in which an oxygen atom is bonded to the xe2x80x9ccyano C1-6 alkyl groupxe2x80x9d as defined above.
The xe2x80x9clower acyl groupxe2x80x9d represented by the above R3 refers to a linear or branched acyl group derived from a fatty acid having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isopvaleryl, pivaloyl and hexanoyl groups.
The xe2x80x9coptionally substituted amino group which may be substitutedxe2x80x9d represented by the above R3 refers an amino group in which the nitrogen atom may be substituted by a group such as a C1-6 alkyl group, including cyclic amino groups. Examples of the xe2x80x9coptionally substituted amino groupxe2x80x9d include amino (xe2x80x94NH2), methylamino (xe2x80x94NHCH3), diemthylamino (xe2x80x94N(CH3)2), pyrrolidinyl, pyrazolinyl, piperidinyl and piperazinyl groups.
The xe2x80x9coptionally substituted amide groupxe2x80x9d represented by the above R3 refers to an amide group in which the nitrogen atom may be substituted by a group such as a C1-6 alkyl group, including amide groups of cyclic amines. Examples of the xe2x80x9coptionally substituted amide groupxe2x80x9d include amide (xe2x80x94CONH2), N-methylamide (xe2x80x94CONHCH3), N,N-dimethylamide (xe2x80x94CON(CH3)2), N-ethylamide (xe2x80x94CONHC2H5), N,N-diethylamide (xe2x80x94CON(C2H5)2), N-methyl-N-ethylamide (xe2x80x94CON(CH3)C2H5), pyrrolidinylcarbonyl, pyrazolinylcarbonyl, piperidinylcarbonyl and piperazinylcarbonyl groups.
The xe2x80x9cC1-6 thioalkoxy groupxe2x80x9d represented by the above R3 refers to a group in which the C1-6 alkyl group as defined above is bonded to a sulfur atom, such as methylthio (xe2x80x94SCH3) and ethylthio (xe2x80x94SC2H5) groups.
In R1 of the above formula (I), the symbol xe2x80x9cmxe2x80x9d is 0 or an integer from 1 to 6, preferably 0 or an integer from 1 to 5, more preferably 0 or an integer from 1 to 3, still more preferably 0 or an integer of 1 or 2, most preferably 0 or 1. The symbol xe2x80x9cnxe2x80x9d is an integer from 1 to 4, preferably an integer from 1 to 3, more preferably an integer of 1 or 2. The symbol xe2x80x9cpxe2x80x9d is an integer of 1 or 2, preferably 1.
In the formula (I), R1 is preferably a group represented by the formula: 
wherein R3, m and n have the same meanings as defined above. In this case, it is more preferred that R1 be hydrogen atom, a halogen atom, hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno C1-6 alkyl group, a hydroxy C1-6 alkyl group, a cyano C1-6 alkyl group, a halogeno C1-6 alkoxy group, a hydroxy C1-6 alkoxy group or a cyano C1-6 alkoxy group; and m be 0 or an integer from 1 to 5. It is still more preferred that R3 be hydrogen atom, a C1-6 alkoxy group, a halogeno C1-6 alkyl group, a halogeno C1-6 alkoxy group, a hydroxy C1-6 alkoxy group or a cyano C1-6 alkoxy group; and m be 0 or an integer from 1 to 3. It is most preferred that R3 be hydrogen atom or a C1-6 alkoxy group (such as methoxy, ethoxy, n-propoxy and i-propoxy group); and m be 0, 1 or 2.
In the formula (I), R2 represents a C3-8 cycloalkylmethyl group, 2,2-(alkylenedioxy)ethyl group or a group represented by the following formula: 
(wherein the ring A is benzene ring or a heterocyclic ring; each R1 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkoxyalkoxy group, an aryloxy group, an aralkyloxy group, a halogeno C1-6 alkyl group, a hydroxy C1-6 alkyl group, a cyano C1alkyl group, a halogeno C1-6 alkoxy group, a hydroxy C1-6 alkoxy group, a cyano C1-6 alkoxy group, a lower acyl group, nitro group, an optionally substituted amino group, an optionally substituted amide group, mercapto group or a C1-6 thioalkoxy group and two of the R5 groups may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and q is 0 or an integer from 1 to 5), provided that such a R2 group is excluded that provides 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine as the 4-substituted piperidine compound fluoride.
The xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d in the xe2x80x9cC3-8 cycloalkylmethyl groupxe2x80x9d represented by the above R2 refers to the C3-8 cycloalkyl group as defined above, and the xe2x80x9cC3-8 cycloalkylmethyl groupxe2x80x9d refers to a group in which the C3-8 cycloalkyl group is bonded to methyl group. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and cyclooctylmethyl groups. Among these, cyclohexylmethyl group is more preferred.
The xe2x80x9c2,2-(alkylenedioxy)ethyl groupxe2x80x9d represented by the above R2 refers to a group in which the terminal carbon atom of an ethyl group is substituted by a cyclic alkylenedioxy group (i.e., an acetal group), such as 2,2-(ethylenedioxy)ethyl (also referred to as 1,3-dioxolan-2-yl]methyl), 2,2-(propylenedioxy)ethyl (also referred to as 1,3-dioxan-2-yl)methyl) and 2,2-(butylenedioxy)ethyl (also referred to as 1,3-dioxepan-2-yl)methyl) groups. Among these groups, 2,2-(ethylenedioxy)ethyl group is more preferred.
The xe2x80x9caryl groupxe2x80x9d in the xe2x80x9caryloxy groupxe2x80x9d represented by the above R5 refers to a cyclic hydrocarbon group forming an aromatic ring structure, including those of mono-, di- and tri-cyclic types, such as phenyl, indenyl, naphthyl, azlenyl, heptalenyl, anthnyl and phenanthrenyl groups. The xe2x80x9caryloxy groupxe2x80x9d refers to a group in which the aryl group is bound to an oxyge atom, such as phenoxy and naphthyloxy groups.
The xe2x80x9caralkyloxy groupxe2x80x9d represented by the above R5 refers to a group in which the aryl group as defined above is bound to a C1-6 alkyl group and the resulting arylalkyl group is further bound to an oxygen atom, such as benzyloxy, phenylethoxy, phenylpropoxy and naphthylmethoxy groups.
The xe2x80x9chalogen atomxe2x80x9d, xe2x80x9cC1-6 alkyl groupxe2x80x9d, xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d, xe2x80x9cC1-6 alkoxy groupxe2x80x9d, xe2x80x9cC1-6 alkoxyalkoxy groupxe2x80x9d, xe2x80x9chalogeno C1-6 alkyl groupxe2x80x9d, xe2x80x9chydroxy C1-6 alkyl groupxe2x80x9d, xe2x80x9ccyano C1-6 alkyl groupxe2x80x9d, xe2x80x9chalogeno C1-6 alkoxy groupxe2x80x9d, xe2x80x9chydroxy C1-6 alkoxy groupxe2x80x9d, xe2x80x9ccyano C1-6 alkoxy groupxe2x80x9d, xe2x80x9clower acyl groupxe2x80x9d, xe2x80x9can optionally substituted amino groupxe2x80x9d, xe2x80x9can optionally substituted amide groupxe2x80x9d and xe2x80x9cC1-6 thioalkoxy groupxe2x80x9d represented by the above R5 have the same definitions as those for the above halogen atom, C1-6 alkyl group, C3-8 cycloalkyl group, C1-6 alkoxy group, C1-6 alkoxyalkoxy group, halogeno C1-6 alkyl group, hydroxy Cl6 alkyl group, cyano C1-6 alkyl group, halogeno C1-6 alkoxy group, hydroxy C1-6 alkoxy group, cyano C1-6 alkoxy group, lower acyl group, an optionally substituted amino group, an optionally substituted amide group and C1-6 thioalkoxy group, respectively. The xe2x80x9cC1-6 alkoxycarbonyl groupxe2x80x9d refers to a group in which the C1-6 alkoxy group as defined above is bound to a carbonyl group, such as methoxycarbonyl (xe2x80x94COOCH3) and ethoxycarbonyl (xe2x80x94COOC2H5) groups.
In the above definition for R5, two R5 groups may together form an aliphatic ring, such as cyclopentane, cyclohexane, cycloheptane and cyclooctane rings; may together form an aromatic ring, such as benzene ring; may together form a heterocyclic ring, such as furan, thiophene, pyrrole, imidazole, oxazole, thizole, triazole, pyridine, pyrazine, pyrimidine, tetrahydrofuran, tetrahydropyran, dioxane, dioxolane, piperidine, piperazine, morpholine and thiomorpholine rings; and may together form an alkylenedioxy ring, such as methylenedioxy, ethylenedioxy and propylenedioxy groups.
In the above R2, the xe2x80x9cheterocyclic ringxe2x80x9d represented by the ring A refers to a ring having 1 to 4 hetero atoms such as nitrogen, sulfur and oxygen atoms, including a xe2x80x9c5- to 14-membered aromatic heterocyclic ringxe2x80x9d and a xe2x80x9c5- to 10-membered non-aromatic heterocyclic ringxe2x80x9d.
1) As the xe2x80x9c5- to 14-membered aromatic heterocyclic ringxe2x80x9d, there may be mentioned, for example, a mono-, di- or tri-cyclic, 5- to 14-membered aromatic heterocyclic ring having 1 to 4 atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms, including: (1) nitrogen-containing aromatic heterocyclic rings such as pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, indole, isoindole, indolidine, purine, indazole, quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine, quisoxaline, quinazoline, cinnoline, pteridine, imidazotriazine, pirazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline and phenasine rings; (2) sulfur-containing aromatic heterocyclic rings, such as thiophene and benzothiophene rings; (3) oxygen-containing aromatic haterocyclic rings, such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran rings; and (4) aromatic heterocyclic rings containing two or more different atoms selected from nitrogen, sulfur and oxygen atoms, such as thiazole, isothiazole, benzthiazole, benzthiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole and pyridoxadine rings.
2) The xe2x80x9c5- to 10-membered non-aromatic heterocyclic ringxe2x80x9d refers to a hydrocarbon ring in which 1 to 4 carbon atoms are substituted by heteroatoms selected from nitrogen, sulfur and oxygen atoms, including unsaturated fused rings. Examples of the xe2x80x9c5- to 10-membered non-aromatic heterocyclic ringxe2x80x9d include pyrrolidine, pyrroline, piperidine, piperazine, imidazoline, pyrazolidine, imidazolidine, morpholine, tetrahydropyran, aziridine, oxirane and oxathiorane rings and phthalimide and succinimide.
3) The ring A is preferably benzene, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperadine or morpholine ring.
In the formula (I) above, R2 is preferably a C3-8 cycloalkylmethyl group or a group represented by the formula: 
(wherein the ring A, R5 and q have the same meanings as defined above), more preferably a group represented by the formula: 
(wherein the ring A, R5 and q have the same meanings as defined above), and still more preferably a group represented by the formula: 
(wherein R5 and q have the same meanings as defined above) provided that such a R2 group is excluded that provides 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine as the 4-substituted piperidine compound fluoride represented by the formula (I).
R1 and R2 in the formula (I) are defined as described above. In the formula (I), each of R1 and R2 can be selected independently from the groups in the definition, respectively, and it goes without saying that R1 and R2 are not limited to a certain combination (provided that such a combination is excluded that provides 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine). The most preferred embodiments of the compound according to the present invention include the following compounds, a salt thereof or hydrates thereof, but it goes without saying that the present invention is not limited to them:
(1) 1-benzyl-4-[(5,6-diethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(2) 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]piperidine;
(3) 1-benzyl-4-[2-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]ethyl]piperidine;
(4) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-fluorobenzyl)piperidine;
(5) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-methylbenzyl)piperidine;
(6) 1-cyclohexylmethyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(7) 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(1,3-dioxolan-2-yl)methylpiperidine;
(8) 1-(4-benzyloxybenzyl)-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine;
(9) 3-(l-benzylpiperidin-4-yl)-2-fluoro-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone;
(10) 3-(1-benzylpiperidin-4-yl)-2,2-difluoro-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone;
(11) 5,7-dihydro-3-[l-fluoro-2-[1-phenylmethyl]-4-piperidinyl]ethyl]-6H-pyrolo[4,5-f]-1,2-benzisooxasol-6-on;
(12) 5,7-dihydro-3-[1,1-difluoro-2-[1-phenylmethyl]-4-piperidinyl]ethyl)-6H-pyrolo[4,5-f]-1,2-benzisooxasol-6-on;
(13) 1-(2-methyl-6-benzothiazoryl)-3-[l-phenylmethyl]-4-piperidinyl]-2-fluoro-1-propanone; and
(14) 1-(2-methyl-6-benzothiazoryl)-3-[1-phenylmethyl]-4-piperidinyl]-2,2-difluoro-1-propanone.
The xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used in the present invention is not particularly limited as long as it is an addition salt formed with the compound of the present invention. Specific examples include: hydroacid salt halides, such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides; inorganic acid salts, such as sulfates, nitrates, perchlorates, phosphates, carbonates and bicarbonates; organic carboxylic acid salts, such as acetates, oxalates, maleates, tartrates and fumarates; organic sulfonates, such as methane sulfonates, trifluoromethane sulfonates, ethane sulfonates, benzene sulfonates, toluene sulfonates and camphor sulfonates; amino acid salts, such as aspartates and glutamates; salts with an amine, such as trimethylamine salts, triethylamine salts, procaine salts, pyridine salts and phenethylbenzylamine salts; alkali metal salts, such sodium salts and potassium salts; and alkali earth metal salts, such as magnesium salts and calcium salts; preferably hydrochlorides and oxalates.
For the production of the compound of the present invention, various processes may be employed. Typically, the following process is employed. It goes without saying that the compound of the present invention can also be produced by another process.
It can be produced by fluorinating the 4-substituted piperidine compound produced according to the process described in, for example, JP-A 64-79151 (EP-296560-A1), JP-A 55-140149 (EP-487071-A1), JP-B 6-500794, JP-B 6-510788, 6-508904, JP-A 5-279355, JP-A 5-320160, JP-A 6-116237 or JP-A 6-41070 and represented by the following formula (II) (provided that 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine is excluded); and, if required, converting it into a salt. 
In the formula, xe2x80x9cRxe2x80x9d represents any group selected from the following substituents: 
(wherein R3, R4, n, m, p and the bond represented by the following formula:

have the same meanings as defined above); and
R2 is has the same meaning as defined above.
In this case, a desirable result can be generally obtained when the starting compound is reacted first with a base and then with a fluorinating gent.
In the production process described above, the base to be used is preferably a strong base, such as lithium bis(trimethylsilyl) amide, n-butyl lithium, lithium diisopropylamide, sodium amide, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide and potassium hydroxide, and is not particularly limited. The fluorinating agent to be used includes, for example, N-fluorobenzenesulfonimide (NFSI, CAS Registration No: 133745-75-2), 3-cyclohexyl-2-fluoro-2,3-dihydro-3-methyl-1,1-dioxide-1,2-benzisothiazole (CMIT-F, CAS Reg. Nos: 186806-24-6, 196106-79-3), 2-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide (CAS Reg. No: 124170-23-6), diethylaminosulfur trifluoride (DAST, CAS Reg. No: 38078-09-0), N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (Ishikawa Reagent), hydrogen fluoride, tetraalkylammonium fluoride, potassium fluoride, cesium fluoride, hydrogen fluoride-pyridine (Olah Reagent) etc. Among these agents, N-fluorobenzenesulfonimide, 3-cyclohexyl-2-fluoro-2,3-dihydro-3-methyl-1,1-dioxide-1,2-benzisothiazole or 2-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide are preferred. The solvent used here is not limited as long as it is inert to the above-mentioned strong bases and fluorinating agents. Specific examples of the solvent include tetrahydrofuran (THF), 1,2-dimethoxyethane (DME; ethylene glycol dimethyl ether), ethyl ether, isopropyl ether, butyl ether, 1,3-dioxane, 1,4-dioxane, 1,3-dioxolane, 1,4-dioxolane, benzene, toluene, xylene, cyclohexane, n-hexane, n-pentane, n-octane and petroleum ether. These solvents may be used singly or as a mixture of two or more of them.
The compound (I) of the present invention can be produced by the process described above. The starting compound in the reaction may in the form of a salt or hydrate, and is not particularly limited as long as it is inert to the reaction. In the case where the compound (I) of the present invention is obtained in a free form, the obtained compound (I) may be converted into a salt which the compound (I) can form by a conventional method. Each of various isomers of the compound (I) of the present invention obtained may be purified and isolated by conventional separation mean (e.g., recrystallization, chromatography, etc.). Particularly in the case where an optically active form of the compound of the present invention is desired, it can be obtained by, for example, any of the following methods.
(1) To use an optically active fluorinating agent.
(2) To resolve racemates optically.
The compound (I) of the present invention may be formulated into tablets, powder, fine granules, granules, coated tablets, capsules, syrup, troche, inhalant, suppository, injection, ointment, ophthalmic ointment, eye drops, nose drops, ear drops, poultice, lotion etc. by a conventional method. In the formulation, there can be used conventional fillers, binders, lubricants, coloring agents and flavoring agents and, if necessary, stabilizing agents, emulsifying agents, absorbefacients, surfactants, pH adjusting agents, preservatives, antioxidants etc. may also be used. In general, the formulation is performed by blending components to used as the raw materials for a pharmaceutical preparation in a conventional manner. For example, for the preparation of for oral administration, the compound of the present invention or a pharmaceutically acceptable salt thereof and a filler and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent etc. are blended together, and then formed into powder, fine granules, granules, tablets, coated tablets, capsules or the like in a conventional manner. The components of these additives include, for example, animal and plant oils such as soy bean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyl dodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hardened castor oil and polyoxyethylene/polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propyleneglycol, dipropyleneglycol and sorbitol; saccharides such as glucose and saccharose; inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; purified water; etc. The filler to be used includes, for example, lactose, corn starch, saccharose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide; the binder includes, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol/polyoxyethylene block polymer and meglumine; the disintegrant includes, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin and calcium carboxymethyl cellulose; the lubricant includes, for example, magnesium stearate, talk, polyethylene glycol, silica and hardened plant oils; the coloring agent includes those substances which are permitted to add to pharmaceutical preparations; and the flavoring agent includes, for example, cocoa powder, menthol, empasm, peppermint oil, borneol and cinammon powder. These tablets or granules may be sugarcoated or coated with other appropriate coating. In the case where a syrup or a preparation for injection is to be prepared, the compound of the present invention or a pharmaceutically acceptable salt thereof may be added with a pH adjusting agent, a resolvent, an isotonizing agent and so on, if necessary, together with a solubilizer, a stabilizing agent and so on, and formulated in a conventional manner. For a pharmaceutical preparation for external application, the process for production of the preparation is not particularly limited and any of the conventional methods may be employed. As the base materials for the preparation, various materials which are conventionally used in drugs, quasi-drugs, cosmetics etc. Specific examples of the base materials to be used include animal and plant oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water etc. If necessary, pH adjusting agents, antioxidant, chelating agents, antiseptical fungicidal agents, coloring agents, flavoring agents and so on may also be added. However, the base materials for external preparations of the present invention are not limited to these materials. If necessary, agents having a differentiation inducing effect, bloodstream promoting agents, germicides, antiphlogistics, cell activators, vitamins, amino acids, moisturizers, keratin solubilizers and so on may also be added. The amounts of the base materials may be those which are employed for formulation of conventional external preparations.
In the administration of a preparation comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, the dosage form is not particularly limited, and may be for oral or parenteral administration through conventional routes. For example, it can be formulated and administered in the dosage form of tablets, powder, granules, capsules, syrup, troche, inhalant, suppository, injection, ointment, ophthalmic ointment, eye drops, nose drops, ear drops, poultice, lotion etc. The dosage of the pharmaceutical preparation of the present invention may be suitably selected depending on the severity of the symptoms, the age, sex and body weight of a patient, the route of the administration, the type of the salt, specific kinds of the disease etc.